Preparation of 1-(lower-alkyl)-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate

ABSTRACT

Lower-alkyl 4-Q-7-methyl-1,8-naphthyridine-3-carboxylates (I) where Q is chloro or lower-alkoxy are prepared by reacting loweralkyl 1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate (II) with a chlorinating agent to produce said 4-chloro compound (Ia) which be reaction with alkali metal lower-alkoxide, preferably using lower-alkanol as solvent, produces said 4(lower-alkoxy) compound (Ib). Said 4-chloro compound when heated with alkali metal lower-alkoxide or said 4-(lower-alkoxy) compound when heated yield the known antibacterially active lower-alkyl 1-(lower-alkyl)-1,4-dihydro-7-methyl-4-oxo-1,8naphthyridine-3-carboxylates.

United States Patent [191 Brundage et al.

[ Dec. 17, 1974 [22] Filed:

[ 4] PREPARATION OF l-(LOWER-ALKYL)-1,4-DlHYDRO-7- METl-lYL-4-OXO-1,8-NAPHTHYRIDINE-3- CARBOXYLATE [75] inventors: R. Pauline Brundage; George Y.

Lesher, Shodack, both of N.Y.

[73] Assignee: Sterling Drug Inc., New York, NY.

June 8, 1973 I [2]] Appl. No.: 368,455

Related US. Application Data [62] Division of Ser. No. 263,788, .lune I9, 1972, Pat. No.

UNITED STATES PATENTS 3,590,036 6/1971 Lesher et a], 260/2955 B Primary ExaminerAlan L. Rotman Attorney, Agent, or FirmRobert K. Bair; B. Woodrow Wyatt 57 ABSTRACT Lower-alkyl 4-Q- 7-methyll ,8-naphthyridine-3- carboxylates (l) where Q is chloro or lower-alkoxy are prepared by reacting lower-alkyl 1,4-dihydro-7- methyl-4-oxol ,8-naphthyridine-3-carboxylate (ll) with a chlorinating agent to produce said 4-chloro compound (la) which be reaction with alkali metal lower-alkoxide, preferably using lower-alkanol as solvent, produces said 4-(lower-alkoxy) compound (lb). Said 4-chloro compound when heated with alkali metal lower-alkoxide or said 4-(lower-alkoxy) compound when heated yield the known antibacterially active lower-alkyl l-(lower-alkyl)-1,4-dihydro-7- methyl-4-oxo-l ,8-naphthyridine-3-carboxylates.

5 Claims, N0 Drawings PREPARATION OF 1-(LOWER-ALKYL)-l,4-DIHYDRO-7-METHYL-4- OXO-l,S-NAPHTHYRIDINE-El-CARBOXYLATE This application is a division of copending application Ser. No. 263,788, filed June 19, 1972, now U.S. Pat. No. 3,786,043, issued Jan. 15, 1974.

This invention relates to lower-alkyl 4-substituted-7- methyl-l,S-naphthyridine-3-carboxylates and to processes for their preparation and utilization as intermediates.

The invention in its composition aspect resides in compounds of the Formula I produce lower-alkyl 4-(lower-alkoxy)-7-methyl-l,8- naphthyridine-3-carboxylate.

The invention in another process aspect resides in the process of heating lower-alkyl 4-chloro-7-methyl-L8- naphthyridine-3-carboxylate with alkali metal loweralkoxide to produce lower-alkyl l-(lower-alkyl)-l,4- dihydro-7-methyl-4-oxo-l ,8-naphthyridine-3- carboxylate. In this reaction the 4-chloro compound is first converted into the corresponding 4-(loweralkoxy) compound which on heatingis converted to the antibacterially active lower-alkyl l-(lower-alkyl)- l,4-dihydro-7-methyl-4-oxol ,8-naphthyridine-3- carboxylate. Thus, this process aspect of the invention also resides in the process of heating lower-alkyl 4- (loweralkoxy)-7-methyl-l ,8-naphthyridine-3- carboxylate to produce a lower-alkyl l-(lower-alkyl)- l,4-dihydro-7-methyl-4-oxo-l ,8-naphthyridine-3- carboxylate.

The processes of the invention are illustrated by the following flowsheet:

where Q is chloro or lower-alkoxy and R is lower-alkyl. These compounds are useful as intermediates in the preparation of lower-alkyl l-( lower-alkyl)-l ,4-dihydro- 7-methyl-4-oxo-l ,8-naphthyridine-3-carboxylates and corresponding 3-carboxylic acids, which are known antibacterial agents.

The invention in a process aspect resides in the process of reacting lower-alkyl l,4-dihydro-7-methyl-4- oxo-l,8-naphthyridine-3-carboxylate with a chlorinating agent, e.g., phosphorus oxychloride, to yield loweralkyl 4-chloro-7-methyl-1,8-naphthyridine-3- carboxylate.

The invention'in another process aspect resides in the process of reacting lower-alkyl 4-chloro-7-methyl-l,8- naphthyridine-3-carboxylate with alkali metal loweralkoxide, preferably using lower-alkanol as solvent, to

III

where M is alkali metal, and R and R are each loweralkyl and can be the same or different. When the reaction of la with MOR' is carried out using as solvent, -lower-alkanol, R"OH where R" is lower-alkyl, the results are as follows:

MOB

H" OH MOR' first reacts with R"OH to produce MOR" which reacts with the 4-chloro compound and the ester exchange reaction between R"OH and the 3COOR compound to produce the 3-COOR" compound also takes place. Similarly, when la is heated with MOR' using ROH as solvent, the resulting product is loweralkyl 1,4-dihydrol -R '-4-oxo-7-CH l ,8- naphthyridine-3-carboxylate (llla), as follows:

I Ia MOE The term lower-alkyl, as used herein, means alkyl groups having from one to six carbon atoms, illustrated by methyl, ethyl, n-propyl, isopropyl, n-butyl, Z-butyl, isobutyl, n-amyl, n-hexyl, and the like.

The term lower-alkoxy," as used herein, means alkoxy groups having from one to six carbon atoms, illustrated by methoxy, ethoxy, n-propoxy, isopropoxy, nbutoxy, 2-butoxy, isobutoxy, n-amoxy, n-hexoxy, and the like.

The intermediate compounds illustrated by Formula ll, exist in tautomeric forms, that is, as the l,4-dihydro- 3-(COOR)-4-oxo-7-CH -l,8-naphthyridines of Formula ll and/or the 3-(COOR)-4-hydroxy-7-Cl-l -1,8- naphthyridines of Formula II, illustrated as follows:

/ coon where R is lower-alkyl. Measurements of the infrared spectra, in potassium bromide admixture, or in chloroform solution or mineral oil suspension, indicate existence predominantly as structure ll and we have preferred to use the names based on structure ll, although it is understood that either or both structures are comprehended.

The molecular structures of the composition aspects of the invention are established by their mode of synthesis and confirmed by the correspondence of calculated and found values for the elementary analyses for representative examples and by infrared, ultraviolet and NMR spectral analyses.

The manner and process of making and using the instant invention will now be generally described so as to enable a person skilled in the art of chemistry to make and use the same as follows:

The reaction of lower-alkyl 1,4-dihydro-7-methyl-4- oxo-l ,8-naphthyridine-3-carboxylate with chlorinating agent, preferably phosphorus oxychloride, to produce lower-alkyl 4-chloro-7-methyl-l ,8-naphthyridine-3- carboxylate is carried out by heating the reactants,

preferably at about 5 0 to 110C. The reaction is conveniently run by heating the reactants with stirring on a steam bath in the absence or presence of an inert solvent, e.g., benzene, toluene, xylene. chlorobenzene. chloroform, methylene dichloride, and thelike. While the preferred chlorinating agent is phosphorus OXyChiO- ride, other chlorinating agents can be used, e.g., phosphorus dichloride, phosphorus pentachloride, thionyl chloride, phenylphosphonic dichloride, phosgene, and the like.

The reaction of lower-alkyl 4-chloro-7-methyl-l,8- naphthyridine-3-carboxylate with alkali metal loweralkoxide to produce lower-alkyl 4-(lower-alkoxy)-7- methyl-l,8-naphthyridine-3-carboxylate is carried out preferably at room temperature, although lower and higher temperatures, from about 0C. up to about 50C. may be used. Said alkali metal lower-alkoxide can be generatedby any of several well known procedures, such as the reaction of an alkali metal or of any alkali organometallic, e.g., phenyllithium, or of a different alkali metal lower-alkoxide with a lower-alkanol. Although this reaction is run preferably with loweralkanol as the solvent, it also can be run by using a solvent inert under the reaction conditions, e.g., acetonitrile, dimethylformamide, tetrahydrofuran, ether, benzene, toluene, chloroform, and the like.

The reaction of lower-alkyl 4-chloro-7-methyl-l,8- naphthyridine-3-carboxylate with alkali metal loweralkoxide to produce lower-alkyl l-(lower-alkyl)-l,4- dihyd'ro-7-methyl-4-oxol ,8-naphthyridine-3- carboxylate is carried out by heating the reactants together. This reaction as well as the conversion of loweralkyl 4-(lower-alkoxy)-7-methyll ,8-naphthyridine-3- carboxylate by heating to produce lower-alkyl l- (lower-alkyl )-l ,4-dihydro-7-methyl-4-oxol ,8 naphthyridine-S-carboxylate are run at about 250C., preferably at about -l 10C., in the absense or presence of a suitable solvent inert under the reaction: conditions, e.g., lower-alkanol, acetonitrile, dimethylformamide, tetrahydrofuran, ether, benzene, toluene, chloroform, and the like. The 4-chloro compound (la) is first converted to the 4-(lower-alkoxy) compound (lb) which then on heating yields the l- (lower-alkyl)-l,4-dihydro-4-oxo compound (Ill). The conversion of lower-alkyl 4-(lower-alkoxy)-7-methyll,8-naphthyridine-S-carboxylate to lower-alkyl l- (lower-alkyl l ,4-dihydro-7-methyl-4-oxol ,8- naphthyridine-3-carboxylate is conveniently run by heating the reactants on a steam bath in the absence of a solvent; however, solvents such as those named above can be used.

The best mode contemplated for carrying out the invention is now set forth as follows:

EXAMPLE 1 Ethyl 4-chloro-7-methyll ,8-naphthyridine-3- carboxylate A mixture containing 10 g. of ethyl l,4- dihydro-4-oxo-7-methyl-1,8-naphthyridine-3- carboxylate and 80 ml. of phosphorus oxychloride was heated at 105C. for seven minutes with stirring. Most of the phosphorus oxychloride was distilled off in vacuo and the residual solution was'poured into a mixture of ammoniumhydroxide and ice. After the mixture had been allowed'to stand for about 45 minutes, the resulting precipitate was collected, washed with water and dissolved in methylene dichloride. The methylene dichloride solution was separated from a small amount of aqueous phase and was dried over anhydrous sodium sulfate. The solution was evaporated in vacuo to near dryness and to the remaining solution was added about 100 ml. of ether. The resulting precipitate was collected and extracted repeatedly with ether. The ether extracts were combined and partially evaporated on a steam bath whereupon a crystalline light orange solid separated. The solid was collected and the filtrate again partially evaporated on a steam bath, yielding asecond crop. The two crops were combined and air-dried to yield 6.3 g. of ethyl 4chloro-7-methyl-l,8- naphthyridine-3-carboxylate, mp. 100C.

EXAMPLEZ Ethyl 4-chloro-7-methyl-1,8-naphthyridine-3- carboxylate A mixture containing 69.6 g. of ethyl l,- 4-dihydro-7-methyl-4-oxol ,8-naphthyridine-3- carboxylate and 550 ml. of phosphorus oxychloride was heated with stirring at 9396C. for 7 minutes. Heating was discontinued and most of the phosphorus oxychloride was distilled off in vacuo. The residue was poured with stirring into a mixture of ice water and ammonium hydroxide. The precipitated product was collected and extracted with 600 ml. of methylene dichloride. The insoluble material was filtered off and the filtrate dried over'anhydrous sodium sulfate. The methylene dichloride solution was concentrated in vacuo to a volume of about 50 ml. and'to the resulting'liquid-solid mixture was added about 800 ml. of ether. The mixture was heated to boiling and the undissolved material was collected. [This undissolved material was extracted with about 800 ml. of boiling ether and filtered to yield a solution containing ethyl 4-chloro-7-methyl-l,8- naphthyridine-3-carboxylate which was used directly in Example 3.] The filtrate was evaporated to about 400 ml. and allowed to stand overnight (about hours). The crystalline precipitate was collected to yield 13 g. of ethyl 4-chloro-7-methyll ,8-naphthyridine-3- carboxylate. The filtrate was concentrated in vacuo to dryness at about 50C. and the residual solid was recrystallized twice from benzene to yield 2.5 g. of ethyl 4-chloro-7-methyl-1,8-naphthyridine-3-carboxylate, which was used directly in Example 4.

EXAMPLE 3 Methyl 4-methoxy-7-methyl-1,8-naphthyridine-3- carboxylate The ether filtrate from Example 2 containing ethyl 4-chloro-7-methyl-1,8-naphthyridine-3- carboxylate was concentrated in vacuo to dryness avoiding 'heat. To the remaining crystalline residue of ethyl 4-chloro-7-methyl-1 ,8-naphthyridine-3- from benzene to yield, as a yellow solid, methyl 4- methoxy-7-methyll ,8-naphthyridine-3-carboxylate, m.p. llO-l 12C. The chemical structure of this compound was confirmed by its NMR (5% in CDCl;,) and UV analyses and by its elemental analyses for C, H and N. A W

EXAMPLE 4 Methyl naphthyridine-3-carboxylate The 2.5 g. portion of ethyl V 4-chloro-7-methyll ,8-naphthyridine-3- carboxylate from Example 2 was dissolved in a solution 'of 0.8 g. of sodium methoxide in 25 ml. of methanol ture; the mixture was filtered; and the filtercake was recrystallized from ethanol to yield, as tan colored nee: dles, 350 mg. of methyl 1,4-dihydro-l ,7 -dimethyl-4- oxo-l ,8-naphthyridine-3-carboxylate, m.p. 200202C. The chemical structure-of this compound was confirmed by its NMR analysis (5% in CDCl;;) and its elemental analyses for C, H and N.

Alkaline hydrolysis of methyl l,4-dihydro-l,7- dimethyl-4-oxol ,8-naphthyridine-3-carboxylate, for example using aqueous potassium hydroxide, a known procedure, yields the corresponding l,4-dihydro-l,7- dimethyl-4-oxo-l,8-naphthyridine-3-carboxylic acid, which is shown as Example 4 in the U.S. Pat. No. 3,590,036, issued June 29', 1971; said patent also shows the intermediate lower-alkyl 4-hydroxy-7-methyl-l,8- naphthyridine-3-carboxylates of Formula II discussed hereinabove.

We claim:

1. The process consisting essentially of heating at about 70250C. in the absence or presence of a suitable solvent inert under the reaction conditions, where the solvent is selected from a polar, dipolar aprotic, and

carboxylate (about 1 g.) was added a solution of about non-polar solvent, lower-alkyl 4-chloro-7-methyl-1,8- naphthyridine-3-carboxylate with alkali metal lower-' alkoxide to produce lower-alkyl l-(lower-alkyl)-l ,4- dihydro-7-methyl-4-oxo-l ,8-naphthyridine-3- carboxylate.

2. The process according to claim 1 Where the reaction is carried out using lower-alkanol as a solvent.

3. The process according to claim 1 wherein ethyl 4- chloro-7-methyl-l ,8-naphthyridine-3-carboxylate is heated with sodium methoxide using methanol as a solvent to produce methyl 1,4-dihydro-l ,7-dimethyl-4- oxol ,S-naphthyridine-3-carboxylate.

4. The process consisting essentially of heating at about 250C. in the absence or presence of a suitable solvent inert under the reaction conditions, where the solvent is selected from a polar, dipolar aprotic, and non-polar solvent, lower-alkyl 4-(lower-alkoxy)-7- methyl-l,8 naphthyridine-3-carboxylate to produce lower-alkyl l-( lower-alkyl )-l ,4-dihydro-7-methyl-4- oxo-l ,8-naphthyridine-3-carboxylate.

5. The process according to claim 4 wherein methyl 4-methoxy-7-methyl- 1 ,8-naphthyridine-3-carboxylate is heated to produce methyl l,4-dihydro-l ,7'dimethyl- 

1. THE PROCESS CONSISTING ESSENTIALLY OF HEAING AT ABOUT 70*-250*C. IN THE ABSENCE OR PRESENCE OF A SUITTING AT ABOUT
 2. The process according to claim 1 where the reaction is carried out using lower-alkanol as a solvent.
 3. The process according to claim 1 wherein ethyl 4-chloro-7-methyl-1,8-naphthyridine-3-carboxylate is heated with sodium methoxide using methanol as a solvent to produce methyl 1,4-dihydro-1,7-dimethyl-4-oxo-1,8-naphthyridine-3-carboxylate.
 4. The process consisting essentially of heating at about 70*-250*C. in the absence or presence of a suitable solvent inert under the reaction conditions, where the solvent is selected from a polar, dipolar aprotic, and non-polar solvent, lower-alkyl 4-(lower-alkoxy)-7-methyl-1,8-naphthyridine-3-carboxylate to produce lower-alkyl 1-(lower-alkyl)-1,4-dihydro-7-methyl-4-oxo-1, 8-naphthyridine-3-carboxylate.
 5. The process according to claim 4 wherein methyl 4-methoxy-7-methyl-1,8-naphthyridine-3-carboxylate is heated to produce methyl 1,4-dihydro-1,7-dimethyl-4-oxo-1,8-naphthyridine-3-carboxylate. 